Compounds comprising a fibroblast activation protein ligand and use thereof

Abstract

The present invention is related to a compound comprising a cyclic peptide of formula (I) and an N-terminal modification group A attached to Xaa1, wherein Xaa1, Xaa2, Xaa3, Xaa4, Xaa5 and Xaa6 are each residues of an amino acid, Xaa7 is a residue of an amino thiol or an amino acid of formula, Yc is a cyclization element which is either present or absent, and the N-terminal modification group A is either a blocking group Abl or an amino acid Aaa.

1 . A compound comprising a cyclic peptide of formula (I) 
       
         
           
           
               
               
           
         
         and an N-terminal modification group A attached to Xaa1, 
         wherein
 the peptide sequence is drawn from left to right in N to C-terminal direction, 
 Xaa1 is a residue of an amino acid of formula (II) 
 
       
       
         
           
           
               
               
           
         
         
            wherein 
         
         R 1a  is —NH— 
         R 1b  and R 1c  are each and independently from each other H or CH 3 ,
 n=0 or 1,
 the N-terminal modification group A is covalently attached to the nitrogen atom of Xaa1, 
 the carbonyl group of Xaa1 is covalently attached to the nitrogen of Xaa2; 
 
 Xaa2 is a residue of an amino acid of formula (III), (IV) or (XX) 
 
       
       
         
           
           
               
               
           
         
         
           wherein 
           R 2a , R 2b  and R 2c  are each and independently selected from the group consisting of (C 1 -C 2 )alkyl and H, wherein said (C 1 -C 2 )alkyl is optionally substituted by a substituent selected from the group consisting of OH, NH 2 , halogen and (C 5 -C 7 )cycloalkyl,
 p=0, 1 or 2 
 v=1 or 2 
 w=1, 2 or 3 and 
 the amino acid of formula (IV) is optionally substituted by one or two substituents each and individually selected from the group consisting of methyl, OH, NH 2  and F at indicated ring positions 3 and/or 4; 
 Xaa3 is a residue of an amino acid of formula (V) or (XX) 
 
         
       
       
         
           
           
               
               
           
         
         
           wherein 
           X 3  is selected from the group consisting of CH 2 , CF 2 , CH—R 3b , S, O and NH, p=1 or 2
 v=1 or 2 
 w=1, 2 or 3, 
 R 3a  is selected from the group consisting of H, methyl, OH, NH 2  and F, 
 R 3b  is selected from the group consisting of methyl, OH, NH 2  and F; 
 
           Xaa4 is a residue of an amino acid of formula (VI) 
         
       
       
         
           
           
               
               
           
         
         
           wherein 
         
         R 4a  is selected from the group consisting of H, OH, COOH, CONH 2 , X 4  and —NH—CO—X 4 , wherein X 4  is selected from the group consisting of (C 1 -C 6 )alkyl, (C 5 -C 6 )aryl and (C 5 -C 6 )heteroaryl, and X 4  is optionally substituted by one or two substituents each and individually selected from the group consisting of methyl, CONH 2 , halogen, NH 2  and OH;
 q=1, 2 or 3, wherein optionally one or two hydrogens of said one, two or three CH 2 -groups are each and individually substituted by methyl, ethyl, (C 5 -C 6 )aryl or (C 5 -C 6 )heteroaryl,
 R 4b  is methyl or H; 
 
 Xaa5 is a residue of an amino acid of structure (VII) 
 
       
       
         
           
           
               
               
           
         
         wherein 
         R 5  is selected from the group consisting of OH and NH 2 , and 
         r=1, 2 or 3;
 Xaa6 is a residue of an amino acid selected from the group consisting of an aromatic L-α-amino acid and a heteroaromatic L-□-amino acid; 
 Xaa7 is a residue of an amino thiol or an amino acid of formula (IX), 
 
       
       
         
           
           
               
               
           
         
         R 7a  is selected from the group consisting of —CO—, —COOH, —CONH 2 , —CH 2 —OH, —(CO)—NH—R 7b , —(CO)—(NR 7c )—R 7b  and H, wherein R 7b  and R 7c  are each and independently (C 1 -C 4 )alkyl and 
         t=1 or 2;
 Yc is a cyclization element of formula (X) which is either present or absent; 
 
       
       
         
           
           
               
               
           
         
         wherein if Yc is absent, the S atom of Xaa1 and the S atom of Xaa7 are covalently linked to each other forming a cyclic structure of formula (XXII) 
       
       
         
           
           
               
               
           
         
         wherein 
         n=0 or 1, 
         t=1 or 2, 
         and 
         wherein if Yc is present, the S atom of Xaa1 is linked to Yc by a thioether linkage and the S atom of Xaa7 is linked to Yc by a thioether linkage forming a cyclic structure of formula (XXI) 
       
       
         
           
           
               
               
           
         
         wherein 
         n=0 or 1, 
         t=1 or 2,
 wherein the N-terminal modification group A is either a blocking group Abl or an amino acid Aaa. 
 
       
     
     
         2 . The compound of  claim 1 , wherein Yc is a structure of formula (XIII): 
       
         
           
           
               
               
           
         
         wherein R c1  is H, (C 1 -C 6 )alkyl or a structure of formula (XI), (XII) or (XXII) 
       
       
         
           
           
               
               
           
         
         wherein R c2  is H or a Z group, wherein the Z group comprises a chelator and optionally a linker, 
         f=1, 2, 3, 4, 5 or 6, 
         g and h are each and independently from each other 1 or 2, 
         i is an integer between 0 and 36, and 
         k=1, 2, 3 or 4. 
       
     
     
         3 . The compound of  claim 2 , wherein R c2  is a Z group comprising a chelator group and optionally a linker, preferably the linker is selected from the group consisting of Ttds, O2Oc, Apac, Gly, Bal, Gab, Mamb, Pamb, Ppac, 4Amc, Inp, Sni, Rni, Nmg, Cmp, PEG6, PEG12 and other PEG-amino acids, preferably from the group consisting of Ttds, O2Oc, Apac, 4Amc, PEG6 and PEG12, and most preferably the linker is selected from the group consisting of Ttds, O2Oc and PEG6. 
     
     
         4 . The compound of  claim 1 , where the blocking group Abl is selected from the group consisting of R a1 —C(O)—, R a1 —S(O 2 )—, R a1 —NH—C(O)— and R a1 —O—C(O)—; wherein R a1  is (C 1 -C 8 )alkyl optionally substituted by up to two substituents each and independently selected from the group consisting of OH, F, COOH, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl and (C 3 -C 8 )heterocycle, and wherein in (C 1 -C 8 )alkyl one of the —CH 2 -groups is optionally replaced by —S— or —O—, preferably the blocking group Ab1 is hexanoyl, Buca-, Buur or pentyl sulfonyl, preferably the blocking group Abl is hexanoyl or Buur. 
     
     
         5 . The compound of  claim 1 , wherein the amino acid Aaa is a D-amino acid residue or an L-amino acid residue each of structure (XIV): 
       
         
           
           
               
               
           
         
         wherein 
         R a2  is selected from the group consisting of (C 1 -C 6 )alkyl, modified (C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl, modified (C 1 -C 3 ), (C 3 -C 8 )carbocycle, aryl, heteroaryl and (C 3 -C 8 )heterocycle, wherein in modified (C 1 -C 6 )alkyl one —CH 2 — group is replaced by —S— or —O—, and in modified (C 1 -C 3 )alkyl one of the H is substituted by OH, F or COOH, or two of the H are substituted by F, preferably Aaa is selected from the group consisting of the amino acid residues of N1e, n1e, Met and met, and their derivatives. 
       
     
     
         6 . The compound of  claim 1 , wherein Xaa1 is a D-amino acid residue selected from the group consisting of cys, hcy and pen, or Xaa1 is an L-amino acid residue selected from the group consisting of Cys, Hcy and Pen, preferably Xaa1 is a D-amino acid residue selected from the group consisting of cys and hcy, or Xaa1 is an L-amino acid residue selected from the group consisting of Cys and Hcy. 
     
     
         7 . The compound of  claim 1 , wherein Xaa2 is an amino acid residue selected from the group consisting of Pro, Gly, Nmg and their derivatives, wherein Xaa3 is an amino acid residue selected from the group consisting of Pro, Hyp, Tfp, Cfp, Dmp, Aze and Pip, and their derivatives, wherein Xaa4 is an amino acid residue selected from the group consisting of Thr, Hse, Asn, Gln and Ser, and their derivatives, wherein Xaa5 is an amino acid residue selected from the group consisting of Gln and Glu, and their derivatives,
 wherein Xaa6 is an amino acid residue of any one of formulae (VIIIa), (VIIIb), (VIIIc) and (VIIId):   
       
         
           
           
               
               
           
         
         wherein 
         R 6a  a and R 6b  are each and independently selected from the group consisting of H, methyl, ethyl, propyl and isopropyl, 
         R 6c  represents from 0 to 3 substituents, each such substituent being each and independently selected from the group consisting of Cl, F, Br, NO 2 , NH 2 , CN, CF 3 , OH, OR 6d  and C 1 -C 4  alkyl, 
         R 6d  is selected from the group consisting of methyl, ethyl, propyl, and isopropyl, 
         s=0 or 1, and 
         wherein Xaa7 is an amino thiol residue selected from the group consisting of Cys, Cysol, AET, Hcy, cys and hcy. 
       
     
     
         8 . The compound of  claim 7 , wherein Xaa6 is an amino acid residue of formula (VIIIa) 
       
         
           
           
               
               
           
         
         wherein R 6c  represents 0 to 2 substituents, each such substituent being each and independently selected from the group consisting of Cl, F, Br, NO 2 , NH 2 , CN, CF 3 , OH, O—R 6d  and methyl, 
         preferably R 6c  represents 0 to 1 substituent, wherein, if present, R 6c  is more preferably bound in ortho or meta position, 
         most preferably Xaa6 is an amino acid residue selected from the group consisting of Phe, Tyr, Ocf and Mcf. 
       
     
     
         9 . The compound of  claim 7 , wherein Xaa6 is an amino acid residue of any one of formulae (VIIIb), (VIIIc) and (VIIId): 
       
         
           
           
               
               
           
         
         wherein R 6c  represents 0 to 2 substituents, each such substituent being each and independently selected from the group consisting of Cl, F, Br, NO 2 , NH 2 , CN, CF 3 , OH, O—R 6d  and methyl, 
         preferably Xaa6 is an amino acid residue selected from the group consisting of Ppa, Mpa, Thi and 1Ni. 
       
     
     
         10 . The compound of  claim 1 , wherein Xaa2 is Pro, Xaa3 is Pro, Xaa4 is Thr, Xaa5 is an amino acid residue selected from the group consisting of Gln and Glu, Xaa6 is Phe, and Xaa7 is an amino thiol residue selected from the group consisting of Cys and Hcy. 
     
     
         11 . The compound of  claim 1 , wherein the compound is a compound of formula (LI), (LII), (LIII) or (LIV): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein X 1  is —NH— or —CH 2 —, and Y 1  is —NH 2  or —OH. 
       
     
     
         12 . The compound of  claim 1 , wherein the N-terminal modification group A is the amino acid Aaa and wherein the compound comprises a Z group covalently attached to the amino acid Aaa, wherein the Z group comprises a chelator and optionally a linker, wherein, if the linker is present, the linker covalently links the chelator to the amino acid Aaa, preferably to the α-nitrogen of the amino acid Aaa, more preferably the covalent linkage between the linker and the α-nitrogen of the amino acid Aaa is an amide, most preferably, the linker is selected from the group comprising Ttds, O2Oc, Apac, Gly, Bal, Gab, Mamb, Pamb, Ppac, 4Amc, Inp, Sni, Rni, Nmg, Cmp, PEG6, PEG12 and other PEG-amino acids. 
     
     
         13 . The compound of  claim 1 , wherein an amino acid or a peptide is attached to Xaa7, wherein a majority of the amino acids of this peptide are charged or polar and the net charge of the peptide is −2, −1, 0, +1 or +2, preferably the peptide is selected from the group consisting of peptides of formula (XXXa-f)
   X aa 10-X aa 11-X aa 12-X aa 13-X aa 14-X aa 15-X aa 16  (XXXa)
 
   X aa 10-X aa 11-X aa 12-X aa 13-X aa 14-X aa 15  (XXXb)
 
   X aa 10-X aa 11-X aa 12-X aa 13-X aa 14  (XXXc)
 
   X aa 10-X aa 11-X aa 12-X aa 13  (XXXd)
 
   X aa 10-X aa 11-X aa 12  (XXXe)
 
   X aa 10-X aa 11  (XXXf)
 
 wherein 
 Xaa10 is Asp, asp, Bal, Gly, Gab, Ser, Nmg, Bhf. Lys, Ttds or Bhk 
 Xaa11 is His, his, Lys, Ttds, Arg, Ape or Ala, 
 Xaa12 is Phe, Nmf, Tic, Aic, Mpa, Amf, Nmf, phe, Lys, Ape, Ttds and Ppa 
 Xaa13 is Arg, Lys, Ape, Ttds or arg, 
 Xaa14 is Asp, Ala, asp, Lys, Ape or Ttds, 
 Xaa15 is Ttds, Ape or Lys, and 
 Xaa16 is Lys or Ape, 
 wherein, optionally, 
 Xaa11 and Xaa12 together form a single amino acid selected from the group consisting of Gab, Pamb, Cmp, Pamb, Mamb, and, optionally, 
 Xaa10, Xaa11 and Xaa12 form together a single amino acid selected from the group consisting of Gab, Pamb, Cmp, Pamb, and Mamb, 
 under the proviso that in the peptides of formulae (XXXa-f) Ape, if present, is the C-terminal building block, 
 and wherein the amino acid attached to Xaa7 is Xaa17, wherein Xaa17 is Asp, asp, Bal, Gly, Gab, Ser, Nmg, Bhf, Lys, Ttds or Bhk, and wherein the α-COOH functionality of Xaa17 is either present as free COOH-group or present as CONH 2 -group, 
 preferably a Z-group is covalently attached to the peptide or 
 to the Xaa17, 
 wherein in each case the Z group comprises a chelator and optionally a linker, 
 more preferably the chelator is covalently linked to amino acid attached to Xaa17 or the chelator is covalently linked to the C-terminal amino acid of the peptide, preferably the C-terminal amino acid of any one of peptide of formulae (LI), (LII), (LIII) and (LIV). 
 
     
     
         14 . The compound of  claim 1 , wherein the chelator is selected from the group consisting of DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, N x S 4-x  (N4, N2 S2, N3 S), Hynic,  99m Tc(CO) 3 -Chelators, more preferably DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4 and most preferred DOTA, DOTAGA, NOTA and NODAGA, preferably the chelator is DOTA. 
     
     
         15 . The compound of  claim 1 , wherein the compound is selected from the group consisting of compound H-Met-[Cys-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH 2  (1001) of the following formula 
       
         
           
           
               
               
           
         
         compound Hex-[Cys-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH 2  (1002) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Ttds-Nle-[Cys-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-NH 2  (1003) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Nle-[Cys-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-NH 2  (1004) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-O2Oc-Nle-[Cys-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH 2  (1005) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Ttds-Nle-[Cys-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH 2  (1006) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Ttds-Nle-[Cys-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Pamb-Arg-NH 2  (1007) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Ttds-Nle-[Cys-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH 2  (1008) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Ttds-Nle-[Cys-Pro-Pro-Thr-Gln-Phe-Cys]-OH (1009) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Ttds-Nle-[Cys-Pro-Pro-Thr-Gln-Phe-Cys]-Bal-OH (1010) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys-Pro-Pro-Thr-Gln-Phe-Cys]-Bhk(DOTA)-OH (1011) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys-Pro-Pro-Thr-Glu-Phe-Cys]-Bhk(DOTA)-OH (1012) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Lys(DOTA)-NH 2  (1013) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Buur-[Cys-Pro-Pro-Thr-Glu-Phe-Cys]-Bhk(DOTA)-OH (1014) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Buur-[Cys-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Lys(DOTA)-NH 2  (1015) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Lys(DOTA)-NH 2  (1016) of the following formula 
       
       
         
           
           
               
               
           
         
         compound NODAGA-Ttds-Nle-[Cys-Pro-Pro-Thr-Gln-Phe-Cys]-Bal-OH (1018) of the following formula 
       
       
         
           
           
               
               
           
         
         compound N4Ac-Ttds-Nle-[Cys-Pro-Pro-Thr-Gln-Phe-Cys]-Bal-OH (1019) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Lys(NODAGA)-NH 2  (1020) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Lys(N4Ac)-NH 2  (1021) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH 2  (2001) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Hcy-Pro-Pro-Thr-Gln-Phe-Hcy]-Asp-NH 2  (2002) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Nle-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH 2  (2003) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-O2Oc-Nle-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH 2  (2004) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Ttds-Nle-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH 2  (2005) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Ttds-Nle-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Pamb-Arg-NH 2  (2006) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Ttds-Nle-[Cys(mli)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-NH 2  (2007) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Ttds-Nle-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-OH (2008) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Ttds-Nle-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Bal-OH (2009) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Bhk(DOTA)-OH (2010) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys(mli)-Pro-Pro-Thr-Glu-Phe-Cys]-Bhk(DOTA)-OH (2011) of the following formula 
       
       
         
           
           
               
               
           
         
         Compound Hex-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Lys(DOTA)-NH2 (2012) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Buur-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Bhk(DOTA)-OH (2013) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Buur-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Lys(DOTA)-NH 2  (2014) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys(mli(Me))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Lys(DOTA)-NH 2  (2015) of the following formula 
       
       
         
           
           
               
               
           
         
         compound DOTA-Ttds-Nle-[Cys(mli(Me))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH 2  (2016) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys(mli(DOTA-Ttd))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH 2  (2017) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys(mli(DOTA-Eda))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH 2  (2018) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys(mli(DOTA-Ttd))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (2019) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys(mli(DOTA-Ttd))-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-NH 2  (2020) of the following formula 
       
       
         
           
           
               
               
           
         
         compound NODAGA-Ttds-Nle-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Bal-OH (2021) of the following formula 
       
       
         
           
           
               
               
           
         
         compound N4Ac-Ttds-Nle-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Bal-OH (2022) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Lys(NODAGA)-NH 2  (2023) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys(mli)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Lys(N4Ac)-NH 2  (2024) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys(mli(NODAGA-Ttd))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH 2  (2025) of the following formula 
       
       
         
           
           
               
               
           
         
         compound Hex-[Cys(mli(N4Ac-Ttd))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH 2  (2026) of the following formula 
       
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 1 , wherein the compound comprises a diagnostically active nuclide or a therapeutically active nuclide, wherein, preferably, the diagnostically active nuclide is a diagnostically active radionuclide, more preferably selected from the group consisting of  43 Sc,  44 Sc,  51 Mn,  52 Mn,  64 Cu,  67 Ga,  68 Ga,  86 Y,  89 Zr,  94m Tc,  99m Tc,  111 In,  152 Tb,  155 Tb,  177 Lu,  201 Tl,  203 Pb,  18 F,  76 Br,  77 Br,  123 I,  124 I,  125 I, preferably  43 Sc,  44 Sc,  64 Cu,  67 Ga,  68 Ga,  86 Y,  89 Zr,  99m Tc,  111 In,  152 Tb,  155 Tb,  203 Pb,  18 F,  76 Br,  77 Br,  123 I  124 I,  125 I and most preferably  64 Cu,  68 Ga,  89 Zr,  99m Tc,  111 In,  18 F,  123 I, and  124 I and wherein the therapeutically active nuclide is a therapeutically active radionuclide, more preferably selected from the group consisting of  47 Sc,  67 Cu,  89 Sr,  90 Y,  111 In,  153 Sm,  149 Tb,  161 Tb,  177 Lu,  186 Re,  188 Re,  212 Pb,  213 Bi,  223 Ra,  225 Ac,  226 Th,  227 Th,  131 I,  211 At, preferably  47 Sc,  67 Cu,  90 Y  177 Lu,  188 Re,  212 Pb,  213 Bi,  225 Ac,  227 Th,  131 L  211 At and most preferably  90 Y,  177 Lu,  225 Ac,  227 Th,  131 I and  211 At. 
     
     
         17 . (canceled) 
     
     
         18 . A composition, preferably a pharmaceutical composition, wherein the composition comprises a compound according to  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         19 . A kit comprising a compound according to  claim 1 , one or more optional excipient(s) and optionally one or more device(s), whereby the device(s) is/are selected from the group comprising a labeling device, a purification device, a handling device, a radioprotection device, an analytical device or an administration device.